Concentrations of reactive oxygen and nitrogen species are high in the expired air, condensed breath and bronchoalveolar lavage fluid of patients with asthma. The bioactivities of many of these compounds in the asthmatic airway are critically dependent on pH in vitro. For example, protonation of nitrite (NO2−) to form nitrous acid (HNO2; pKa˜3.3) and protonation of peroxynitrite (ONOO−) to form peroxynitrous acid (ONOOH; pKa˜6.3) converts relatively inert salts into highly cytotoxic species. These acids may cause substantial injury to the airway epithelium, largely through the generation of free radicals according to reactions (1) and (2).2H++2NO2−→2HNO2→H2O+.NO2+.NO  (1)H++ONOO−→ONOOH→.OH+.NO2  (2)
Because of the pH-dependent cytotoxicity of chemical species present in high concentrations in the asthmatic airway, the pH of expired water in subjects with acute asthma was studied. This water was condensed during tidal breathing. Samples were filtered during collection (0.3 μm) and were deareated with argon to eliminate artifact caused by variable carbon dioxide tensions. pH values were highly reproducible and unrelated to salivary pH, to nebulizer therapy or to gastroesophageal reflux history.
The mean pH in subjects with acute asthma was over two log orders lower than in controls (7.65±0.20 vs. 5.23±0.21; n=19 and 22, respectively, p<0.001; representing in excess of 100 fold increase in proton/hydronium (H3O+) concentration). These findings are consistent with evidence for low nasal epithelial pH in patients with rhinitis and with bronchoalveolar lavage acidification in ovalbumin-sensitized guinea-pigs. Furthermore, endogenous administration of an acid aerosol to human and animal airways is an effective and reproducible method for creating asthma symptoms. Specifically, an acid aerosol treatment causes airway smooth muscle constriction and airway epithelial injury, classic features of an acute attack of asthma. Moreover, low airway pH causes the death of inflammatory cells lining the airway with release of toxic mediators that perpetuate inflammation and bronchoconstriction, and likely contributes to elevated levels of nitric oxide found in the exhaled breath of asthmatic patients.
Increased serum and airway ECP levels and increased nitric oxide (NO) production/nitrogen oxide (NOx) toxicity have both been considered markers for worsening asthmatic airway inflammation. These effects of airway acidification thus provide not only a theoretical model explaining cytotoxicity and airflow obstruction in asthma exacerbations, but also describe the specific findings observed during asthma exacerbations in general. Of note, several respiratory epithelial cell functions, such as ciliary motility, are also impaired at low pH, and airway mucous production is increased. It has not previously been suspected that these elements of asthma pathophysiology could be stimulated by endogenous airway acidification.
Endogenous acidification of airway lining fluid may be beneficial during certain infections as an innate host defense mechanism. However, in patients with asthma, this process could be expected to aggravate airway inflammation. Our evidence suggests two important mechanisms by which this acidification selectively affects asthmatic subjects. First, acidification may selectively injure the asthmatic airway through toxification of reactive chemical species. Second, necrosis of resident airway eosinophils caused by a fall in pH will lead release of inflammatory mediators such as eosinophil cationic protein.